Relation between circulating levels of GH,IGF-1, ghrelin and somatic growth in Rett syndrome

Background

Most cases of Rett syndrome (RTT) are caused by mutations in methyl CpG binding protein 2 (MECP2), and individuals with RTT have somatic growth failure, growth arrest of brain, epilepsy, and intellectual disability (ID). Ghrelin is a peptide hormone which stimulates growth hormone (GH) secretion from the pituitary gland. Ghrelin and GH regulate insulin-like growth factor-1 (IGF-1) synthesis, and this GH/IGF-1 axis is an endocrine axis involved in energy and sleep homeostasis and plays crucial roles in somatic and brain growth. This study aimed to determine whether circulating ghrelin, GH and IGF-1 reflect somatic and brain growth in RTT patients. Methods: We examined anthropometric data and circulating ghrelin, GH, and IGF-1 in 22 female RTT patients with epilepsy and ID (RTT-Ep/ID) and 14 age-matched females with epilepsy and ID (non-RTT-Ep/ID). Results: Body mass index (BMI) and height/length were significantly lower in RTT-Ep/ID than in non-RTT-Ep/ID in patients less than 20 years old. Plasma ghrelin in RTT-Ep/ID patients showed a significant inverse correlation with weight but had no significant correlations with BMI or height. Head circumference in both groups showed a significant positive correlation with circulating ghrelin and a significant negative correlation with circulating IGF-1. The ratio of octanoyl-ghrelin to total-ghrelin (O/T-ratio) is used as an indicator to estimate the biological activity of ghrelin. Among pre-adolescents, O/T-ratios were significantly higher in the RTT-Ep/ID group than in the non-RTT-Ep/ID group (P < 0.05). Conclusions: Timing of growth-spurts differed between the RTT-Ep/ID and non-RTT-Ep/ID groups, possibly due to a common (but yet unknown) mechanism of growth failure. Ghrelin/GH/IGF-1 axis function was aberrant in both the RTT-Ep/ID and non-RTT-Ep/ID groups. The initial clinical course of Rett syndrome affects the development of the sleep–wake cycle and locomotion in early infancy, both of which may be based on the dysfunction of the aminergic neurons modulated by ghrelin/GH/IGF-1 axis. Further study with a larger sample size should help clarify the precise mechanisms controlling the somatic growth and hormonal features in Rett syndrome.     

Insulin-like growth factor-1 (IGF-1)-induced inhibition of growth hormone secretion is associated with sleep suppression

The hypothalamic growth hormone (GH)-releasing hormone (GHRH) promotes non-rapid eye movement sleep (NREMS). Insulin-like growth factor-1 (IGF-1) acts as a negative feedback in the somatotropic axis inhibiting GHRH and stimulating somatostatin. To determine whether this feedback alters sleep, rats and rabbits were injected intracerebroventricularly (i.c.v.) with IGF-1 (5.0 and 0.25 microgram, respectively) and the sleep-wake activity was studied. Compared to baseline (i.c.v. injection of physiological saline), IGF-1 elicited prompt suppressions in both NREMS and rapid eye movement sleep (REMS) in postinjection hour 1 in rats and rabbits. The intensity of NREMS (characterized by the slow wave activity of the EEG by means of fast-Fourier analysis) was significantly enhanced 7 to 11 h postinjection in rats. Plasma GH concentrations were measured in 30-min samples after i.c.v. IGF-1 injection in rats and a significant suppression of GH secretion was observed 30 min postinjection. The simultaneous inhibition of the somatotropic axis and sleep raises the possibility that the sleep alterations also result from an IGF-1-induced suppression of GHRH. The late increases in NREMS intensity are attributed to metabolic actions of IGF-1 or to a release of GHRH from the IGF-1-induced inhibition.     

Changes in expression of the genes for the leptin receptor and the growth hormone-releasing peptide/ghrelin receptor in the hypothalamic arcuate nucleus with long-term manipulation of adiposity by dietary means

Changes in leptin and ghrelin levels occur with alterations in adiposity, but signalling may be affected by levels of the relevant receptors. We measured expression of the leptin receptor (Ob-Rb) and the ghrelin/growth hormone releasing peptide receptor (GHS-R) in the arcuate nucleus of sheep held at either high or low levels of adiposity. Plasma growth hormone (GH) levels were lower in Fat animals and higher in Lean animals. Plasma insulin and leptin levels were higher in Fat animals and lower in Lean animals. Frozen hypothalamic sections of arcuate nucleus were extracted and mRNA levels measured for mRNA for Ob-Rb and GHS-R. Gene expression for both Ob-Rb and GHS-R was higher in Lean animals than in Fat animals, with no difference in expression between Fat and Normal animals. A second group of animals (n = 4 per group) was used for double-labelling immunohistochemistry to determine whether the increase in Ob-Rb gene expression was translated into Ob-Rb protein and to ascertain whether this effect is localised to the cells of the arcuate nucleus that produce either neuropeptide Y (NPY) and/or pro-opiomelanocortin-derived peptides. Lean animals displayed a 255% increase in immunoreactive NPY cells (P < 0.005), a 167% increase in cells with Ob-Rb (P < 0.037) protein and a 344% increase in cells that were staining for both NPY and Ob-Rb (P < 0.02). There was no difference between the Normal and Lean animals in the number of cells that were detected with an adrenocorticotrophic hormone (ACTH) antibody or the number of ACTH-immunoreactive cells that also stained for Ob-Rb. Finally, we measured plasma ghrelin levels in Normal, Fat and Lean ewes (n = 4/group); levels were higher (P < 0.05) in Fat animals than in Lean animals. We conclude that lowering body weight leads to increased expression of Ob-Rb, ghrelin/GHS-R expression and proportion of NPY cells that express Ob-Rb in the arcuate nucleus. This may be an adaptive mechanism to increase responsivity to both leptin and ghrelin.     

Restricted growth and insulin-like growth factor-1 deficiency in mice lacking presenilin-1 in the neural crest cell lineage

Presenilin-1 (PS1) is a transmembrane protein that is in many cases responsible for the development of early-onset familial Alzheimer's disease. PS1 is essential for neurogenesis, somitogenesis, angiogenesis, and cardiac morphogenesis. We report here that PS1 is also required for maturation and/or maintenance of the pituitary gland. We generated PS1-conditional knockout (PS1-cKO) mice by crossing floxed PS1 and Wnt1-cre mice, in which PS1 was lacking in the neural crest-derived cell lineage. Although the PS1-cKO mice exhibited no obvious phenotypic abnormalities for several days after birth, reduced body weight in the mutant was evident by the age of 3–5 weeks. Pituitary weight and serum insulin-like growth factor (IGF)-1 level were also reduced in the mutant. Histologic analysis revealed severe atrophy of the cytosol in the anterior and intermediate pituitary lobes of the mutant. Immunohistochemistry did not reveal clear differences in the expression levels of thyroid-stimulating hormone, adrenocorticotropic hormone, or prolactin in the mutant pituitary. In contrast, growth hormone expression levels were reduced in the anterior lobe of the mutant. PS1 was defective in the posterior lobe, but not the anterior or intermediate lobes, in the mutant pituitary. These findings suggest that PS1 indirectly mediates the development and/or maintenance of the anterior and intermediate lobes in the pituitary gland via actions in other regions, such as the posterior lobe.     

Dopamine receptor sensitivity in the hypothalamus of chronic schizophrenics after haloperidol therapy: Growth hormone and prolactin response to stimuli

(1) The present investigation deals with a study of the hypothalamic dopamine-receptor sensitivity in schizophrenics, before and after haloperidol therapy, examined by investigation of basal GH and PRL levels and responses to an l-DOPA stimulation test. (2) Ten chronic schizophrenics, 8 males and 2 females, aged 27–53 yr, with a duration of illness from 4 to 32 yr, were studied after they were off therapy for at least 10 days. (3) The l-DOPA stimulation test was done at the beginning of the study and again 3 and 6 days after withdrawal of haloperidol which had been administered in increasing doses from 5 to 10 mg a day for 30 days. l-DOPA was given orally at a dose of 500 mg plus carbidopa 100 mg. (4) Patients were tested psychologically before and after haloperidol therapy by the Asberg Psychopathological Rating Scale and typed genetically for the HLA-SD system. (5) Basal prolactin levels before and after haloperidol therapy were low. GH secretion in response to l-DOPA was normal before haloperidol therapy. (6) After treatment the patients could be divided into two groups according to the HLA types; one group showing an increased response to the stimuli as compared with the other. The data are correlated with the psychological effectiveness of the therapy.     

Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer's disease

Interest in characterizing the role of impaired insulin actions in Alzheimer's disease (AD) and vascular dementia is growing exponentially. This review details what is currently known about insulin, insulin-like growth factor type I (IGF-I) and IGF-II proteins and their corresponding receptors in the brain, and delineates the major controversies pertaining to alterations in the expression and function of these molecules in AD. The various experimental animal models generated by over-expression, mutation, or depletion of genes that are critical to the insulin or IGF signaling cascades are summarized, noting the degrees to which they reproduce the histopathological, biochemical, molecular, or behavioral abnormalities associated with AD. Although no single model was determined to be truly representative of AD, depletion of the neuronal insulin receptor and intracerebroventricular injection of Streptozotocin reproduce a number of important aspects of AD-type neurodegeneration, and therefore provide supportive evidence that AD may be caused in part by neuronal insulin resistance, i.e. brain diabetes. The extant literature did not resolve whether the CNS insulin resistance in AD represents a local disease process, or complication/extension of peripheral insulin resistance, i.e. chronic hyperglycemia, hyperinsulinemia, and Type 2 diabetes mellitus. The available epidemiological data are largely inconclusive with regard to the contribution of Type 2 diabetes mellitus to cognitive impairment and AD-type neurodegeneration. A major conclusion drawn from this review is that there is a genuine need for thorough and comprehensive study of the neuropathological changes associated with diabetes mellitus, in the presence or absence of superimposed AD or vascular dementia. Strategies for intervention may depend entirely upon whether the CNS disease processes are mediated by peripheral, central, or both types of insulin resistance.     

Chemokine receptor deficiency is associated with increased chemokine expression in the peripheral and central nervous systems and increased resistance to herpetic encephalitis

Herpes simplex virus type 1 (HSV-1) infection of the eye leads to the retrograde spread of the virus from the eye to the trigeminal ganglion resulting in the infiltration of leukocytes and production of inflammatory cytokines and chemokines including CXCL9 and CXCL10. The present study investigated the role of the receptor for CXCL9 and CXCL10 in the host response to HSV-1 infection using mice deficient in CXCR3 expression (CXCR3-/-). Although wild type C57BL/6 and CXCR3-/- mice cleared the virus, HSV-1 titers remained elevated in the ganglion and brain stem of CXCR3-/- mice day 7 post infection. Coinciding with the increase in virus titer, CCL5, CXCL9, CXCL10 and IFN-gamma protein levels were enhanced in the trigeminal ganglion and/or brain stem of the CXCR3-/- mice associated with a 2-fold increase in the percentage of CD3+CD8+ T lymphocytes in the trigeminal ganglion. However, the survival rate of CXCR3-/- mice was significantly enhanced above the wild type controls associated with an increase in brain IL-6 content. Collectively, the results indicate the absence of CXCR3 is associated with a transient increase in virus burden in the nervous system and an elevated protective immune response.     

Induction of cell growth by insulin and insulin-like growth factor-I is associated with jun expression in the otic vesicle

The present report investigates the cellular mechanisms involved in the regulation of cell proliferation by insulin and insulin-like growth factor-I (IGF-I) in the developing inner ear. The results show that insulin and IGF-I stimulate cell proliferation in the otic vesicle. This effect is associated with the induction of the expression of the nuclear proto-oncogene c-jun. The temporal profile of Jun expression coincided with the proliferative period of growth of the otic vesicle. IGF-I promoted the hydrolysis of a membrane glycosyl-phosphatidylinositol, which was characterised as the endogenous precursor for inositol phosphoglycan (IPG). Both purified IPG and a synthetic analogue, 6-O-(2-amino-2-deoxy-α-D-glucopyranosyl)-D-myo-inositol-1,2-cyclic phosphate (C3), were able to mimic the effects of IGF-I on Jun expression. Anti-IPG antibodies blocked the effects of IGF-I, which were rescued by the addition of IPG or its analogue. These results suggest that the sequence involving the hydrolysis of membrane glycolipids and the expression of c-jun and c-fos proto-oncogenes is part of the mechanism that activates cell division in response to insulin and IGF-I during early organogenesis of the avian inner ear. The implications of these observations for otic development and regeneration are briefly discussed. J. Comp. Neurol. 398:323–332, 1997. © 1998 Wiley-Liss, Inc.     

Insulin-like growth factor type 1 receptor signaling in the cells of oligodendrocyte lineage is required for normal in vivo oligodendrocyte development and myelination

Insulin-like growth factor-I (IGF-I) has been shown to be a potent agent in promoting the growth and differentiation of oligodendrocyte precursors, and in stimulating myelination during development and following injury. To definitively determine whether IGF-I acts directly on the cells of oligodendrocyte lineage, we generated lines of mice in which the type 1 IGF receptor gene (igf1r) was conditionally ablated either in Olig1 or proteolipid protein expressing cells (termed IGF1R(pre-oligo-ko) and IGF1R(oligo-ko) mice, respectively). Compared with wild type mice, IGF1R(pre-oligo-ko) mice had a decreased volume (by 35-55%) and cell number (by 54-70%) in the corpus callosum (CC) and anterior commissure at 2 and 6 weeks of age, respectively. IGF1R(oligo-ko) mice by 25 weeks of age also showed reductions, albeit less marked, in CC volume and cell number. Unlike astrocytes, the percentage of NG2(+) oligodendrocyte precursors was decreased by approximately 13% in 2-week-old IGF1R(pre-oligo-ko) mice, while the percentage of CC1(+) mature oligodendrocytes was decreased by approximately 24% in 6-week-old IGF1R(pre-oligo-ko) mice and approximately 25% in 25-week-old IGF1R(oligo-ko) mice. The reduction in these cells is apparently a result of decreased proliferation and increased apoptosis. These results indicate that IGF-I directly affects oligodendrocytes and myelination in vivo via IGF1R, and that IGF1R signaling in the cells of oligodendrocyte lineage is required for normal oligodendrocyte development and myelination. These data also provide a fundamental basis for developing strategies with the potential to target IGF-IGF1R signaling pathways in oligodendrocyte lineage cells for the treatment of demyelinating disorders.     

Peptide- and transmitter-containing neurons in the mediobasal hypothalamus and their relation to GABAergic systems: possible roles in control of prolactin and growth hormone secretion

Indirect immunofluorescence histochemistry was used to study the relation among GABAergic, catecholaminergic, cholinergic, and peptidergic neurons in the rat mediobasal hypothalamus. By employing a direct double-labelling procedure using sheep antiserum against glutamic acid decarboxylase (GAD), mouse monoclonal and rabbit antibodies to neurotensin (NT) and rabbit antisera to tyrosine hydroxylase (TH), choline acetyltransferase (ChAT), galanin (GAL), growth hormone-releasing factor (GRF), or somatostatin (SOM), it was demonstrated that GAD-positive fibers and terminals in the external part of the median eminence co-contained immunoreactivity for TH, NT, GAL or GRF, but not for SOM. In the internal part of the median eminence-infundibular stalk, GAD-positive/NT-, GAL-, and GRF-negative and GAD-positive/TH-positive fiber plexa were shown. When a recently developed direct triple-labelling procedure with biotin-conjugated mouse secondary antibodies in conjunction with diethylaminocoumarin (DAMC)-conjugated avidin was employed, presence of GAD/GAL/NT- as well as GAD/GRF/NT-containing varicosities could be demonstrated close to hypophysial portal vessels. In colchicine-pretreated animals, GAD was shown to coexist with TH, NT, or GAL in cell bodies in both the dorsomedial and ventrolateral domains of the arcuate nucleus, but with GRF only in the ventrolateral division. ChAT-positive neurons in the ventrolateral region were also TH-positive. In the ventrolateral arcuate nucleus, triple-labelling followed by elution-restaining showed GAD/NT/GAL/TH-immunoreactivities in the same cells. Similarly, double-labelling with two following elution-restaining steps showed several NT/GAL/GRF/TH-containing cell bodies in this part of the arcuate nucleus. GAD-positive cells in the anterior hypothalamic periventricular area and fibers in the pituitary neurointermediate lobe were also TH-positive. The results demonstrate complex patterns of storage of chemical messengers in neurons of the arcuate nucleus-median eminence complex. Possible neuroendocrine interactions of these systems in the control of prolactin and growth hormone secretion are discussed.     

Islet-1 expression and its colocalization with luteinising hormone, thyroid-stimulating hormone and oestrogen receptor alpha in the developing pituitary gland of the sheep foetus

Islet-1 has been reported to be involved in pituitary development in the early stages of mouse embryogenesis. Oestrogen receptor (ER) and its expression may be involved in regulating pituitary development and its hormone-secreting function. Islet-1 expression and its correlations to ER in the developing pituitary gland are unknown. We therefore determined the pituitary cell specific expression of Islet-1 and its colocalization with ER alpha (ERalpha) in sheep foetus by immunohistochemistry. The results demonstrated that Islet-1-immunoreactive (ir) cells were distributed throughout the pituitary gland from day 60 of gestation until birth. The Islet-1-ir cell number was significant higher at day 90 and 120 of gestation compared to that at day 60 and at birth. All of the ERalpha-ir cells were colocalized with Islet-1 at day 60 of gestation, although a few ERalpha-ir cells were negative for Islet-1 in the later stage of gestation. The dominant cell type expressing Islet-1 is the gonadotroph, although small proportions of thyrotrophs and lactotrophs also express Islet-1. The proportion of luteinising hormone-ir gonadotrophs possessing Islet-1 kept rising from day 60 to day 120 of gestation and persisted until birth. The proportion of thyroid-stimulating hormone-ir cells expressing Islet-1 was at a high level from day 60-120 of the gestation and significantly declined at birth. The percentage of prolactin (PRL)-ir cells expressing Islet-1 was about 20% at day 60 of gestation. Very few PRL-ir cells contained Islet-1 in later stages of gestation. These data suggest that the development and functional establishment of pituitary gonadotrophs, thyrotrophs and lactotrophs might be regulated by the expressions of Islet-1 and ERalpha and by their interactions, although any mechanisms need to be elucidated further.     

Ischemia-induced neuronal cell loss is associated with loss of atypical angiotensin type-1 receptor expression in the gerbil hippocampal formation

The hippocampal formation of Mongolian gerbils expresses high amounts of atypical angiotensin II type-1 receptors. We studied the expression of these receptors by in situ hybridization using specific [³⁵S]-labeled riboprobes and by receptor autoradiography using [¹²⁵I]Sarcosine¹-angiotensin II. Angiotensin II receptor mRNA was found in the pyramidal cell layer of the CA1, CA2 and CA3 subfields, with the highest expression in the CA2 subfield, and in the granular cell layer of the dentate gyrus. Angiotensin II binding was detected in the stratum oriens and stratum radiatum of the CA1 and CA2 subfields, in the stratum oriens of the CA3 subfield, and in the molecular layer of the dentate gyrus. We then studied the effect of ischemia on hippocampal angiotensin II receptor expression, 1, 4 and 15 days after bilateral occlusion of the common carotid arteries for 5 min. No changes in angiotensin II receptor mRNA or binding were detected 1 day after ischemia. Delayed, progressive loss of angiotensin II mRNA and binding occurred 4 and 15 days after ischemia, in the CA1, CA2 and CA3 subfields. The decline was faster in the CA1 subfield, and paralleled the loss of neurons after ischemia. In the dentate gyrus, angiotensin II receptor mRNA and angiotensin II binding were not changed when compared to sham operated controls. The decrease of angiotensin II receptor expression may reflect the loss of angiotensin II receptor-producing neurons rather than a down-regulation of receptor expression.     

The role of the mu(1) opioid receptor subtype in the regulation of prolactin and growth hormone secretion by Beta-endorphin in female rats: studies with naloxonazine

The μ opioid receptor subtype has been reported to mediate the prolactin secretory response to opioids. This receptor subtype has been implicated in the morphine-induced prolactin increase, as well as the prolactin response to μ-specific opioid peptides. Subtypes of the μ receptor have been proposed and the μ(1) , site has been postulated as the receptor subtype involved in the morphine-induced prolactin secretory response. However, the role of this receptor subtype in mediating the endocrine effects of the endogenous opioid peptides has not been characterized. In order to determine the physiological significance of this receptor subtype, animals were pretreated with saline, WIN 44,441-3 (a μ, δ and κ antagonist) or naloxonazine (a μ(1) antagonist) followed by a stimulatory dose of morphine or β-endorphin. A dose response study for β-endorphin was conducted to determine the minimal stimulatory dose of β-endorphin on the prolactin and growth hormone (GH) secretory response. The dose response study indicated that β-endorphin is a more potent stimulus for prolactin release than for GH. A dose as low as 25 ng increased prolactin levels as much as 100-fold in both lactating and diestrous female rats. In contrast, 2.5 μg β-endorphin was required in order to consistently and significantly increase circulating levels of GH by 2- to 3-fold. WIN 44,441-3 antagonized the stimulatory effects of β-endorphin on both prolactin and GH secretion. Naloxonazine pretreatment abolished the morphine-induced prolactin secretory response, without affecting the GH increase in diestrous females. Naloxonazine also antagonized the prolactin response to β-endorphin in both lactating and diestrous females. In addition, it attenuated the GH secretory response but did not totally abolish it. These data indicate that β-endorphin elicits an increase in prolactin release through an opioid specific receptor which appears to be the μ(1) opioid receptor subtype. They further suggest that β-endorphin may increase GH levels, at least partially, via its action at this μ(1) site.     

Impact of thyroid hormone deficiency on the developing CNS: cerebellar glial and neuronal protein expression in rat neonates exposed to antithyroid drug propylthiouracil

The developing rat cerebellum is vulnerable to thyroid hormone (TH) deficiency. The present study addresses the molecular mechanisms involved in this response. Specifically, the study focuses on the expression of selected cerebellar proteins that are known to be directly [protein expressing 3-fucosyl-N-acetyl-lactosamine antigen (CD15), neuronal cell adhesion molecule (L1)] or indirectly [glial fibrillary acidic protein (GFAP)], involved in glial-neuronal interactions and thus regulation of cell proliferation and granule cell migration. Cerebellar mass, structure, and protein expression in rat neonates exposed to antithyroid drug propylthiouracil (PTU) from the embryonic day (E) 16 to postnatal day (P) 21 were compared against rat neonates that received replacement of thyroxin (T4) starting on day P1 or untreated controls. Cerebellar proteins were analyzed by quantitative Western blots. PTU-treated rats lagged in growth and showed reduction in cerebellar mass and alterations in cerebellar structure on P15. Daily treatment of neonates with T4 restored normal cerebellum-to-body-mass ratio, cerebellar structure, and cerebellar protein expression. Densitometric analysis of Western blots revealed altered expression of selected proteins in the cerebella of hypothyroid neonates. A decrease of CD15 (46%, p = 0.031) was observed on P10 and was accompanied by a decrease in GFAP expression (64%, p = 0.039). Furthermore, a shift in the developmental GFAP profile was observed in the PTU-treated cerebellum. L1 expression was not significantly affected in the hypothyroid cerebellum. Altered expression of cerebellar proteins is likely to affect cell-cell interactions and consequently cell proliferation and migration and contribute to structural and functional alterations seen in the hypothyroid rat neonates.     

Neonatal exposure to estradiol prevents the expression of ovarian hormone-induced luteinizing hormone and prolactin surges in adulthood but not antecedent changes in neuropeptide Y or adrenergic transmitter activity: Implications for sexual differentiation of gonadotropin secretion

Sex differences in adult patterns of mating behavior and gonadotropin secretion in rats are determined in part by the presence or absence of gonadal steroids during a perinatal critical period. For example, male rats and female rats exposed neonatally to androgen do not exhibit LH surge patterns when treated appropriately with ovarian hormones in adulthood, and there is evidence that this may be due to a failure of ovarian hormones to activate the hypothalamic neuronal systems that stimulate LH secretion in such animals. Because considerable evidence suggests that estradiol formed centrally from testosterone is responsible for the permanent defeminization of mating behavior and gonadotropin secretion, the present studies compared normal females with normal males and with females treated neonatally with estradiol on the ability of ovarian hormones to induce several important neurochemical changes antecedent to the LH surge, including changes in neuropeptide Y (NPY) and LH-releasing hormone (LHRH) concentrations in the median eminence, as well as changes in turnover rates for catecholamine transmitters in the medial basal hypothalamus and medial preoptic area. Normal ovariectomized female rats responded to sequential treatment with estradiol followed by progesterone with afternoon LH and prolactin (PRL) surges, and with sequential accumulation followed by decline in concentrations of LHRH and NPY in the median eminence prior to the LH surge. In addition, administration of progesterone increased the turnover rates of norepinephrine (NE) and epinephrine (EPI) in the arcuate-median eminence region of normal females. Gonadectomized male rats receiving the same ovarian hormone treatment failed to exhibit LH or PRL surges and displayed none of the changes in neurotransmitter turnover or peptide concentrations characteristically seen in the normal female. Unexpectedly however, when females that were treated with estradiol benzoate on days 1–3 postpartum were ovariectomized and treated with ovarian hormones in adulthood, they showed the same accumulation/decline in median eminence NPY concentrations and the same activation of NE and EPI turnover in the arcuate-median eminence region as normal females, even though they showed no LH or PRL surges or changes in median eminence LHRH concentrations. These results suggest that estradiol may not mediate all of the defeminizing actions of androgen exerted during the early neonatal period, and particularly those actions that result in a lack of responsiveness in central noradrenergic, adrenergic and NPY systems in adulthood. However, an action of neonatal estradiol may result in uncoupling of the LHRH neurosecretory system from normal excitatory neurochemical influences.     

Chronic administration of morphine is associated with a decrease in surface AMPA GluR1 receptor subunit in dopamine D1 receptor expressing neurons in the shell and non-D1 receptor expressing neurons in the core of the rat nucleus accumbens

The nucleus accumbens (Acb) is an extensively studied neuroanatomical substrate of opiate reward and the neural plasticity associated with chronic opioid use. The cellular mechanisms mediating opioid-dependent plasticity are uncertain, however AMPA-type glutamate receptor trafficking in dopamine D1 dopamine receptor (D1R) expressing neurons may be a potential cellular pathway for these adaptations, although there is no evidence for this possibility. Immunogold electron microscopy was used to quantify the surface expression of the AMPA GluR1 subunit in dendritic profiles of neurons in the Acb in response to intermittent 14-day non-contingent injections of escalating doses of morphine, a model that parallels opioid self-administration. To determine if changes in GluR1 trafficking occurred in neurons potentially sensitive to dopamine-induced D1R activation, immunoperoxidase labeling of D1R was combined with immunogold labeling of GluR1. Immunogold quantification was performed in two distinct Acb subregions, the shell, an area involved in processing incentive salience related to rewarding stimuli, and the core, an area involved in reward-seeking behaviors. We provide the first report that chronic morphine administration is associated with a receptor-phenotypic decrease in surface trafficking of GluR1 in Acb subregions. When compared to saline injected animals, morphine produced a decrease in plasma membrane GluR1 labeling in medium- and large-sized D1R expressing dendritic profiles in the Acb shell. In contrast, in the Acb core, surface GluR1 was decreased in small-sized dendrites that did not express the dopamine receptor. These results indicate that chronic intermittent injection of escalating doses of morphine is accompanied by ultrastructural plasticity of GluR1 in neurons that are responsive to glutamate and dopamine-induced D1R activation in the Acb shell, and neurons capable of responding to glutamate but not D1R receptor stimulation in the Acb core. Thus, AMPA receptor trafficking associated with chronic opiate exposure in functionally distinct areas of the Acb may be distinguished by D1R receptor activation, suggesting the potential for differing neural substrates of reward and motor aspects of addictive processes involving glutamate and dopamine signaling.     

Resident-intruder trait aggression is associated with differences in lysine vasopressin and serotonin receptor 1A (5-HT1A) mRNA expression in the brain of pre-pubertal female domestic pigs (Sus scrofa)

Aggressive behaviour exhibited by domestic pigs following encounters with unfamiliar individuals is a serious welfare and economical problem. Aggression resulting in skin lesions is similarly prevalent in prepubertal pigs of either sex. Little is known about the neural circuits and neuropeptides that control aggression in the pig. Because there is evidence for the involvement of the vasopressin and serotonergic systems in the regulation of aggressive behaviour in male mammals, we sought differences using quantitative in situ hybridisation of vasopressin and serotonin 1A receptor (5-HT1A) mRNA expression within specific brain regions of aggressive and nonaggressive prepubertal female pigs. The number of cells expressing vasopressin mRNA was significantly higher in aggressive pigs in the medial amygdala, lateral septum (LS) and showed a similar trend in the bed nucleus of the stria terminalis (BnST) but not the paraventricular nucleus (PVN) or supraoptic nucleus. The 5-HT1A receptor was widely expressed through the porcine brain and a significantly lower intensity (silver grain density) of 5-HT1A mRNA expression was observed in the BnST. In the medial amygdala and LS fewer cells expressed 5-HT1A mRNA in aggressive pigs but no differences were found in the PVN. In the absence of inbred strains or selection lines, these findings have shown that prior identification of phenotypic behavioural extremes in a population in advance of neural studies is a useful technique. Moreover, these findings support a central role for vasopressin and serotonin in the mediation of high trait aggression in prepubertal female pigs.     

Social hedonic capacity is associated with the A118G polymorphism of the mu-opioid receptor gene (OPRM1) in adult healthy volunteers and psychiatric patients

A large body of evidence links altered opioid signaling with changes in social behavior in animals. However, few studies have attempted to determine whether similar links exist in humans. Here we investigate whether a common polymorphism (A118G) in the mu-opioid receptor gene (OPRM1) is associated with alterations in personality traits linked to affiliative behavior and attachment. In a mixed sample (N?=?214) of adult healthy volunteers and psychiatric patients, we analyzed the association between the A118G polymorphism of the OPRM1 and two different psychological constructs reflecting individual differences in the capacity to experience social reward. Compared to individuals expressing only the major allele (A) of the A118G polymorphism, subjects expressing the minor allele (G) had an increased tendency to become engaged in affectionate relationships, as indicated by lower scores on a self-report measure of avoidant attachment, and experienced more pleasure in social situations, as indicated by lower scores on a self-report measure of social anhedonia. The OPRM1 variation accounted for about 3.5% of the variance in the two measures. The significant association between the A118G polymorphism and social hedonic capacity was independent of the participants' mental health status. The results reported here are in agreement with the brain opioid hypothesis of social attachment and the established role of opioid transmission in mediating affiliative behavior.